Obg-like ATPase 1 exacerbated gemcitabine drug resistance of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a poor prognosis due to inefficient diagnosis and tenacious drug resistance. Obg-like ATPase 1 (OLA1) is overexpressed in many malignant tumors. The molecular mechanism of OLA1 underlying gemcitabine (GEM)-induced drug resistance was investigated in this study. An enhanced expression of OLA1 was observed in a GEM acquired resistant pancreatic cancer cell lines and in patients with pancreatic cancer. Overexpressed OLA1 showed poor overall survival rates in patients with pancreatic cancer. Dysregulation of the OLA1 reduced expression of CD44+/CD133+, and improved the sensitivity of pancreatic cancer cells to GEM. OLA1 highly expression facilitated the formation of the OLA1/Sonic Hedgehog (SHH)/Hedgehog-interacting protein (HHIP) complex in nuclei, resulting in the inhibition of negative feedback of Hedgehog signaling induced by HHIP. This study suggests that OLA1 may be developed as an innovative drug target for an effective therapy of pancreatic cancer.

Strategy for Comprehensive Detection and Annotation of Gut Microbiota-Related Metabolites Based on Liquid Chromatography-High-Resolution Mass Spectrometry.

Gut microbiota, widely populating the mammalian gastrointestinal tract, plays an important role in regulating diverse pathophysiological processes by producing bioactive molecules. Extensive detection of these molecules contributes to probing microbiota function but is limited by insufficient identification of existing analytical methods. In this study, a systematic strategy was proposed to detect and annotate gut microbiota-related metabolites on a large scale. A pentafluorophenyl (PFP) column-based liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method was first developed for high-coverage analysis of gut microbiota-related metabolites, which was verified to be stable and robust with a wide linearity range, high sensitivity, satisfactory recovery, and repeatability. Then, an informative database integrating 968 knowledge-based microbiota-related metabolites and 282 sample-sourced ones defined by germ-free (GF)/antibiotic-treated (ABX) models was constructed and subsequently used for targeted extraction and annotation in biological samples. Using pooled feces, plasma, and urine of mice for demonstration application, 672 microbiota-related metabolites were annotated, including 21% neglected by routine nontargeted peak detection. This strategy serves as a useful tool for the comprehensive capture of the intestinal flora metabolome, contributing to our deeper understanding of microbe-host interactions.

Maturation of the gut metabolome during the first year of life in humans.

The gut microbiota is involved in the production of numerous metabolites that maintain host wellbeing. The assembly of the gut microbiome is highly dynamic, and influenced by many postnatal factors, moreover, little is known about the development of the gut metabolome. We showed that geography has an important influence on the microbiome dynamics in the first year of life based on two independent cohorts from China and Sweden. Major compositional differences since birth were the high relative abundance of Bacteroides in the Swedish cohort and Streptococcus in the Chinese cohort. We analyzed the development of the fecal metabolome in the first year of life in the Chinese cohort. Lipid metabolism, especially acylcarnitines and bile acids, was the most abundant metabolic pathway in the newborn gut. Delivery mode and feeding induced particular differences in the gut metabolome since birth. In contrast to C-section newborns, medium- and long-chain acylcarnitines were abundant at newborn age only in vaginally delivered infants, associated by the presence of bacteria such as Bacteroides vulgatus and Parabacteroides merdae. Our data provide a basis for understanding the maturation of the fecal metabolome and the metabolic role of gut microbiota in infancy.

Crosstalk between Breast Milk N-Acetylneuraminic Acid and Infant Growth in a Gut Microbiota-Dependent Manner.

The healthy growth of infants during early life is associated with lifelong consequences. Breastfeeding has positive impacts on reducing obesity risk, which is likely due to the varied components of breast milk, such as N-acetylneuraminic acid (Neu5Ac). However, the effect of breast milk Neu5Ac on infant growth has not been well studied. In this study, targeted metabolomic and metagenomic analyses were performed to illustrate the association between breast milk Neu5Ac and infant growth. Results demonstrated that Neu5Ac was significantly abundant in breast milk from infants with low obesity risk in two independent Chinese cohorts. Neu5Ac from breast milk altered infant gut microbiota and bile acid metabolism, resulting in a distinct fecal bile acid profile in the high-Neu5Ac group, which was characterized by reduced levels of primary bile acids and elevated levels of secondary bile acids. Taurodeoxycholic acid 3-sulfate and taurochenodeoxycholic acid 3-sulfate were correlated with high breast milk Neu5Ac and low obesity risk in infants, and their associations with healthy growth were reproduced in mice colonized with infant-derived microbiota. Parabacteroides might be linked to bile acid metabolism and act as a mediator between Neu5Ac and infant growth. These results showed the gut microbiota-dependent crosstalk between breast milk Neu5Ac and infant growth.

Effect of Breastmilk Microbiota and Sialylated Oligosaccharides on the Colonization of Infant Gut Microbial Community and Fecal Metabolome.

The complex microbiota and sialylated oligosaccharides in breastmilk are important bioactive components that affect the gut microbiota. However, the effect of breastmilk microbiota and sialylated oligosaccharides on the gut microbiota during the neonatal period has been largely overlooked. Here, 16S rRNA gene sequencing and metabolomics analysis were applied to the breastmilk and feces of 69 newborns to clarify the link between breastmilk components and the newborn gut. Results showed that Staphylococcus, Enterococcus, and Bacteroides were commonly shared and positively correlated between breastmilk and the neonatal intestine and they were the main bacteria of breastmilk that interacted with the newborn fecal metabolome. Breastmilk Staphylococcus mainly interacted with amino acids, whereas Bacteroides was involved in the tryptophan, nucleotide, and vitamin metabolism. Breastmilk sialylated oligosaccharides were related to Bacteroides and amino acids of the newborn fecal metabolites. Moreover, Bacteroides was related to the interaction between breastmilk 3'-sialyllactose and newborn fecal metabolites in the mediation effect models. Finally, we pointed out that breastmilk Bacteroides was important in the milk-gut interaction, and it was negatively associated with waist circumference in infants aged 1 year. Our study provides a scientific basis for understanding the role of breastmilk in the development of newborn gut microbiota and metabolome.

MetEx: A Targeted Extraction Strategy for Improving the Coverage and Accuracy of Metabolite Annotation in Liquid Chromatography-High-Resolution Mass Spectrometry Data.

Liquid chromatography-high-resolution mass spectrometry (LC-HRMS) is the most popular platform for untargeted metabolomics studies, but compound annotation is a challenge. In this work, we developed a new LC-HRMS data-targeted extraction method called MetEx for metabolite annotation. MetEx contains the retention time (tR), MS1, and MS2 information of 30 620 metabolites from freely available spectral databases, including MoNA and KEGG. The tR values of 95.4% of the compounds in our database were calculated by the GNN-RT model. The MS2 spectra of 39.4% compounds were also predicted using CFM-ID. MetEx was initially examined on a mixture of 634 standards, considering chemical coverage and accurate metabolite assignment, and later applied to human plasma (NIST SRM 1950), human urine, HepG2 cells, mouse liver tissue, and mouse feces. MetEx correctly assigned 252 out of 253 standards detected in our instruments. The platform also provided 8.0-44.2% more compounds in the biological samples compared to XCMS, MS-DIAL, and MZmine 2. MetEx is implemented and visualized in R and freely available at http://www.metaboex.cn/MetEx.

Metabolomics insights into the prenatal exposure effects of polybrominated diphenyl ethers on neonatal birth outcomes.

BACKGROUND: Effects of polybrominated diphenyl ethers (PBDEs) on neonatal birth outcomes vary across previous studies, and the related mechanism investigation remains poorly understood, especially at the metabolic level. OBJECTIVES: To evaluate the associations between prenatal PBDEs exposure and neonatal birth outcomes including gestational age, neonatal weight, birth length, head circumference (HC), Apgar score at 1 min (Apgar1) and 5 min, and further reveal the underlying metabolic disorders in a population-based birth cohort study. METHODS: Gas chromatography-triple quadrupole tandem mass spectrometry (GC-MS/MS) based targeted method and GC-MS based untargeted method were respectively conducted to obtain PBDE levels and metabolic profiles of 200 placental tissue samples from a typical e-waste recycling area (Guiyu) and reference area (Haojiang) in China. Spearman correlation and regression analyses were applied to assess the associations between the placental PBDE levels and birth outcomes. Metabolome-wide association studies and the meet-in-the-middle approach were employed to explore disruptions linking PBDE exposures and the corresponding adverse birth outcomes. RESULTS: Eight out of 27 PBDE congeners were detected in placenta with more than 50% frequency in at least one district and significantly higher in Guiyu than those in Haojiang. The lower HC and Apgar1 had significant associations with PBDE exposures after adjustment for potential confounders. A total of 66, 16 and 14 metabolites were significantly correlated with PBDE exposures, HC and Apgar1, respectively. 4 and 12 PBDE-related metabolites were significantly associated with the risks of decreasing neonatal HC and Apgar1. The disrupted metabolites were mainly involved in the pentose phosphate pathway, ascorbate metabolism, threonine metabolism, butanoate metabolism, lipid metabolism, and arginine biosynthesis. CONCLUSIONS: In this birth cohort, higher placental PBDE levels were significantly associated with the lower HC and Apgar1. The associations might be modified by multiple metabolic disturbances through increasing oxidative stress, mediating neurotoxicity, maternal gut microbiota dysbiosis and vasodilatation regulation.

[Advances in integrase regulations of bacteria--A review].

Because the integrase of class 1 integron in bacteria has been demonstrated closely relative with antimicrobial resistance, we summarize in this review the discussions on some regulation factors with expression of the integrase, such as antibiotics, carbon catabolite repression (cAMP-CRP complex), the promoter of gene cassette variants (Pc-P2 combinations), attC sites, some nucleotide-associated proteins, and the length of variable region. Furthermore, we also provide knowledge of the regulation mechanism of integrase, as well as insight into controlling the dissemination of antimicrobial resistance in the environments.